ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.378C>T (p.Arg126=)

gnomAD frequency: 0.00188  dbSNP: rs145324823
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079436 SCV000262329 benign Colorectal cancer, susceptibility to, 10 2021-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000759962 SCV000518018 likely benign not provided 2021-06-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000427145 SCV000596491 likely benign not specified 2016-07-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000427145 SCV000601942 benign not specified 2017-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000570853 SCV000670887 likely benign Hereditary cancer-predisposing syndrome 2015-07-16 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics,PreventionGenetics RCV000427145 SCV000806539 benign not specified 2017-06-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759962 SCV000889686 benign not provided 2017-06-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000427145 SCV000918074 benign not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: POLD1 c.378C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 276646 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 119 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen RCV000759962 SCV001335080 likely benign not provided 2021-10-01 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000570853 SCV002534677 likely benign Hereditary cancer-predisposing syndrome 2021-05-07 criteria provided, single submitter curation
True Health Diagnostics RCV000570853 SCV000788147 likely benign Hereditary cancer-predisposing syndrome 2018-02-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356191 SCV001551289 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLD1 p.Arg126= variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs145324823) as "With other allele" and ClinVar (classified as benign by Invitae and one other clinical laboratory; and as likely benign by GeneDx, Ambry Genetics, and two other clinical laboratories). The variant was identified in control databases in 468 of 276646 chromosomes (2 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5 of 23978 chromosomes (freq: 0.0002), Other in 12 of 6456 chromosomes (freq: 0.002), Latino in 69 of 34412 chromosomes (freq: 0.002), European in 252 of 126308 chromosomes (freq: 0.002), Finnish in 128 of 25720 chromosomes (freq: 0.005), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg126= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center RCV000759962 SCV001920082 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000759962 SCV001970952 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000427145 SCV002551871 likely benign not specified 2021-10-12 no assertion criteria provided clinical testing

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